Biocompatible, biodegradable polyurethane materials with controlled hydrophobic to hydrophilic ratio

ABSTRACT

The biocompatible, biodegradable materials in the solid and/or liquid form are based on segmented linear polyurethanes and/or segmented crosslinked polyurethanes based on A) one or more biocompatible polyols susceptible to hydrolytic and/or enzymatic degradation having a molecular weight of 100 to 20,000 dalton and a number of active hydroxyl groups per molecule (functionality) of at least two or higher: B) one or more diisocyanates and/or triisocyanates; and C) one or more low molecular weight chain extenders having a molecular weight of 18 to 1000 dalton and the functionality of at least two or higher.

This application is a continuation of U.S. application Ser. No.13/914,549, filed Jun. 10, 2013 (now allowed), which is a continuationof U.S. application Ser. No. 11/572,648, filed Apr. 7, 2008, now U.S.Pat. No. 8,460,378, which is a National Stage Entry of InternationalApplication No. PCT/CH04/00471, filed Jul. 26, 2004, published asWO2006/010278 on Feb. 2, 2006, each of which are incorporated herein byreference in their entirety.

The invention relates to biocompatible, biodegradable materialsaccording to the preamble of claim 1.

The advantages achieved by the invention are essentially to be seen inthe fact that the polyurethane according to the invention can beproduced with a controlled elasticity, i.e. can be either stiff orelastic depending on the intended application of the material. Thepolyurethane materials according to the invention can also be madeinjectable which enhances their implantation using syringes or othersuitable devices for cement delivery. The chemical structure of thepolyurethane materials according to the invention can be designed as toenhance interaction with cells and tissues and ensure controlleddegradation. The material can readily be transformed into porousscaffolds for tissue repair and engineering using available productiontechniques.

Linear and/or crosslinked biodegradable, segmented polyurethanescontaining labile and/or biologically active moieties andpolyurethaneacrylates are produced from biocompatible polyols or themixtures of polyols having various hydrophilicity, aliphaticdiisocyanates, various chain extenders, having preferably but notexclusively biological activity and biocompatible acrylates containingat least one hydroxyl group. The use of aliphatic diisocyanates avoidsproblems with carcinogenic diamines which are formed upon degradation ofpolyurethanes based on aromatic diisocyanates, e.g. 4,4′-diphenylmethanediisocyanate. The use of mixtures of polyols with varioushydrophilicities allows producing materials with controlledhydrophilic-to-hydrophobic content ratio and degradation rates, the useof chain extenders or polyols having biological activity, enhancespositive interaction of implantable devices from the polyurethanes ofthe invention with cells and tissues and may promote tissue healing andregeneration, and the use of hydroxyacrylates in combination withmentioned above reagents allows for the preparation of injectablematerials with adjustable rigidity, e.g. for the treatment ofosteoporotic vertebrae, spine disc diseases or large bone defects. Thepolyurethanes of the invention may contain various additives of organicand inorganic origin to additionally enhance their mechanical andbiological properties.

The biologically active moieties can be chemically incorporated in thepolymer back bone constituting a part of its structure, can be attachedto the backbone as pending fragments, e.g. forming a branched system, orcan be physically attached to the materials using the physicalinteractions such as ionic interaction, adhesion, capillarity effect ordiffusion.

This invention relates to biocompatible, biodegradable polyurethane andpolyurethaneacrylate materials with controlled elastic properties,hydrophilicity, degradation rates and porosity, to be used inimplantable medical devices or as topical wound covers.

Depending on the chemical composition, elastic properties,hydrophilicity, degradation rates and porosity, the polyurethanes andpolyurethaneacrylates of the invention can be used as adhesion barriers,scaffolds for the repair and regeneration of various tissues, solidtissue defect fillers and liquid injectable materials which solidifyafter injection.

Polyurethanes are a weft-known class of materials with thecharacteristic —NH—CO—O-linkage in the chain. The polymers are obtainedin the reaction of diisocyanates with oligomeric diols also calledpolyols to produce a macrodilsocyanate or a prepolymer, and thesynthesis is completed by re-acting macrodiisocyanates with lowmolecular weight two-functional or more-functional chain extenders:2O═C═N—R—N═C═O+HO—(R′)_(n)—OH→O═C═N—R—NH—CO—O—(R′)_(n)—O—O—OC—HN—R—N═C═ODiisocyanate Polyol Prepolymer (macrodiisocyanate)O═C═N—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—N═C═O+HO—R″—OH→Prepolymer Diol—[—O—R″—O—OC—HN—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—NH—CO—O—R″—O—]_(x)-PolyurethaneO═C═N—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—N═C═O+H₂N—R″—NH₂→PrepolymerDiamine→-[HN—R″—NH—CO—NH—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—NH—CO—HN—R″—NH—]_(x)-Polyurethaneurea

Polyols used in the synthesis have molecular weights in the range of 100to 20,000 dalton (preferably 200 to 10,000 dalton) and are primarilybased on polyesters or polyethers, although diols of other oligomericcompounds are also used to produce polyurethanes. The chain extendersare low molecular weight diols, diamines, triols, triamines or highermolecular weight oligomeric units having the functionality of two orhigher. The use of two-functional chain extenders leads tothermoplastic, linear block copolymers of the (AB) type, while the useof three-functional chain extenders such as triols, friar mines or waterleads to crosslinked materials. The structure of segmented polyurethanesconsists of the relatively flexible soft segment derived from polyols,and the hard segments containing diisocyanate and chain extenderspecies. Preferably the hard segment content is in the range of 5 to100% and the soft segment forms the remaining part of the polyurethanematerial.

High-purity medical segmented polyurethanes with a wide range ofphysical and chemical properties are used in various extracorporeal andimplantable devices. One of the problems with implantable polyurethanesis their relatively poor molecular stability in the aggressiveenvironment of the body tissues. Degradation of polyurethanes in vivoproceeds mainly through hydrolytic chain scission within ester andurethane linkages and oxidative attack within polyether segments. Thisappears to be accelerated by the action of cell enzymes, peroxides, thecatalytic activity of metal ions, the formation of carboxylic groups,lipids pickup, calcification, the stress or load acting on the implants,phagocytosis and lysis of material fragments by macrophages and giantcells.

Susceptibility of polyurethanes to in vivo degradation can deliberatelybe exploited to design biodegradable polyurethane materials.Biodegradable polyurethanes can be synthesized by incorporating in thepolymer chain labile moieties, susceptible to hydrolysis and/or tospecific enzymes.

Depending on the mechanical properties, chemical composition and surfacecharacteristics of biodegradable polyurethanes they can potentially beused for cardiovascular implants, drug delivery devices, nonadhesiveharriers in trauma surgery, bone graft substitutes, injectableaugmentation materials, tissue—organ regeneration scaffolds (tissueengineering), or adhesives.

The type of monomers used in the syntheses of biodegradablepolyurethanes will to a great extent be dependent on the intendedapplication of the material. Hydrophilic polyurethane elastomers arepreferred for the preparation of implants to be used in contact withblood or as adhesion barriers, although the ratio between thehydrophilic and hydrophobic components in polyurethanes seems to play animportant role in the contact of the material surface with bloodproteins and cells. The polyurethanes based on polyethylene oxide arehighly hydrophilic materials. At higher polyethylene oxide content,these polymers in the aqueous environment behave like hydrogels, takingup to 200% of water depending on their chemical composition. They arenonadhesive to proteins, cells and tissues. Thus, polyurethanes withhigher amounts of hydrophobic component may be required for bone graftsubstitutes and for cell culture. It should be kept in mind, however,that hydrophobicity is only one of many characteristics, which determinethe interaction of polyurethanes with cells and tissues.

Polyurethaneacrylates can be produced from urethane prepolymers byreacting them with acrylates containing at least one hydroxyl group. Thereaction yields a prepolymer terminated with acrylic linkage:2O═C═N—R—N═C═O+HO—(R′)_(n)—OH→Diisocyanate PolyolO═C═N—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—N═C═O Urethane prepolymer(macrodilsocyanate)O═C═N—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—N═C═O+HO—CH₂CH₂OCOCH═CH₂→Urethaneprepolymer (macrodiisocyanate) hydroxyacrylateO═C═N—R—NH—CO—O—(R′)_(n)—O—OC—HN—R—NHCOO—CH₂CH₂OCOCH═CH₂Urethane-acrylate prepolymer

This can be subsequently polymerized by chemically-induced orradiation-induced free-radical polymerization.

Commodity commercial acrylic urethanes are used as one and two-componentcoatings for weatherable applications. Biodegradable acrylic urethanesof this invention based on biocompatible labile polyols can findapplications as injectable bone substitutes and tissue void fillers.

There were various biodegradable polyurethanes described in thepublished literature. The labile moieties used in the synthesis of thesepolyurethanes were for example polyols from lactic acid and ethylenediol and/or diethylene diol, lactic acid and 1,4-butanediol, butyricacid and ethylene diol, monomers containing peptide links, sugarderivatives, hydroxy-terminated copolymers of L-lactide-ε-caprolactone,glycolide-ε-caprolactone, ε-caprolactone-co-δ-valerolactone, lysinediisocyanate or L-lysine, polyethylene oxide), poly(ε-caprolactone) andamino acid-based chain extender.

The polyurethane materials according to the invention may be linearand/or crosslinked biodegradable, segmented polyurethanes andpolyurethaneacrylates containing labile and/or biologically activemoieties. These material may be used as implantable medical devicescontaining such polyurethanes. The biodegradable polyurethanes of theinvention are based on biocompatible polyols or the mixtures of polyolshaving various hydrophilicity allowing producing materials withcontrolled hydrophilic-to-hydrophobic content ratio, preferably althoughnot exclusively aliphatic diisocyanates or triisocyanates, various chainextenders, having preferably but not exclusively biological activity,and/or biocompatible hydroxyacrylates.

The polyurethane-acrylate material is preferably chosen from:cyclohexane dimethanol dimethacrylate, cyclohexane dimethanoldiacrylate, alkoxylated hexanediol diacrylate, alkoxylated cyclohexanedimethanol diacrylate, caprolactone modified neopentylglycolhydroxypivalate diacrylate, ethylene glycol dimethacrylate,tetraethylene glycol dimethacrylate, polyethylene glycol dimethacrylate,1,4-butanediol diacrylate, 1,4-butanediol dimethacrylate, diethyleneglycol diacrylate, diethylene glycol dimethacrylate, 1,6-hexanedioldiacrylate, 1,6-hexanediol dimethacrylate, neopentyl glycol diacrylate,neopentyl glycol dimethacrylate, polyethylene glycol diacrylate,tetraethylene glycol diacrylate, dipropylene glycol diacrylate,polyethylene glycol dimethacrylate, polyethylene glycol diacrylate,polyethylene glycol dimethacrylate water solution, propoxylated2-neopentyl glycol diacrylate, alkoxylated aliphatic diacrylate.

The biocompatible, biodegradable materials may also be based on:aliphatic urethane acrylates, polyester acrylates, polyether acrylates,amine modified polyether acrylates.

The biocompatible, biodegradable materials are typically based on atleast to two polyols and preferably at least two of said polyols have adifferent hydrophilicity.

In one embodiment all of said polyols are hydrophilic, in anotherembodiment all of said polyols are hydrophobic. However, said polyolsmay also be a mixture of hydrophilic and hydrophobic polyols. The ratiobetween hydrophilic monomers and hydrophobic monomers are preferably inthe range of 1-4, preferably between 2.0-2.6.

Alternatively at least one polyol may have amphiphilic qualities. Thematerials become amphiphilic as a result of their architecture, i.e.chemical constitution resulting from the balance between hydrophilic andhydrophobic segments or groups in the polymeric chain upon synthesis.

The biocompatible polyols which are used separately or as mixtures inthe synthesis of the polyurethanes and polyurethaneacrylates of theinvention have molecular weights in the range of 100 to 20,000 dalton,preferably 400 to 12,000 dalton, and most preferably 400 to 6000 dalton.The polyols are based on polyesters, polyethers, mixtures thereof, andcopolymers of esters with ethers.

The polyols suitable for the synthesis of the polyurethanes of theinvention are based on hydroxyacids or dicarboxylic acids, the examplesof which are lactic acid, citric acid, tartaric acid, adipic acid,succinic acid, sebacic acid, oxalic acid, tannic acid, aspartic acid andazelaic acid. These can be used individually or as a mixture, and diolssuch as 1,4-butanediol, dipropylene diol, ethylene diol, diethylenediol, 1,5-hexanediol and 1,3-propanediol, neopentyl diol, trimethylenediol, and pentaerythritol, to mention but a few. Other polyols can bepolycarbonate diols, poly(ε-caprolactone) diols, poly(ethylene oxide)diols, poly(ethylene oxide-propylene oxide-ethylene oxide) diols knownas commercial product under a trade name Pluronics™, polyols based onβ-propiolactone, δ-valerolactone and γ-butyrolactone, isosorbide,aminosaccharides and polyols from vegetable oils such and micellarcasein as stearic, oleic, linoleic and linolenic for example.

The polyols suitable for the invention have a low molecular stability,which is the inherent ability of the polyol to undergo hydrolytic chainscission in the aqueous environment. When such polyol units areincorporated in polyurethanes, the hydrolytic chain scission proceedsmainly via ester or ether linkages in the polymer chain, dependingwhether polyether diols or polyester diols were used in the polyurethanesynthesis. In polyurethanes water reacts with a carboxylic ester link,which breaks the polymer chain into two shorter ones. One of these endsis a hydroxyl group, while the other end is a carboxyl group. The acidiccarboxyl group accelerates the further hydrolysis of the polyestersegments and the degradation becomes autocatalytic. The urethane(carbamate) linkage can also be hydrolyzed, but less readily thancarboxylic) ester linkages. In polyetherurethanes the ether linkage isrelatively resistant to hydrolysis but can be hydrolyzed in theaggressive environment of the living organism. The weakest linkagetowards hydrolysis of polyetherurethanes is the urethane linkage.Breakage of the urethane linkage produces two shorter chains terminatedwith hydroxyl and amino groups.

The diisocyanates and polydiisocyanates suitable for the synthesis ofthe polyurethanes of the invention are aliphatic or aromaticdiisocyanates, triisocyanates or polyisocyanates. They can be usedindividually or as mixtures in various proportions. Examples ofaliphatic diisocyanates are 1,6-hexamethylene diisocyanate,1,4-diisocyanato butane, L-lysine diisocyanate, isophorone diisocyanate,1,4-diisocyanato 2-methyl butane, 2,3-diisocyanato 2,3-dimethyl butane,1,4-di(1propoxy-3-diisocyanate, 1,4-diisocyanato 2-butene,1,10-diisocyanato decane, ethylene diisocyanate, 2,5 bis(2-isocyanatoethyl) furan, 1,6-diisocyanato 2,5-diethyl hexane, 1,6-diisocyanato3-methoxy hexane, 1,5 diisocyanato pentane, 1,12-dodecamethylenediisocyanate, 2 methyl-2,4 diisocyanato pentane, 2,2 dimethyl-1,5diisocyanato pentane, ethyl phosphonyl diisocyanate,2,2,4-trimethyl-1,6-hexamethylene diisocyanate. Examples of aromaticdiiscocyanates are 4,4′-diphenylmethane diisocyanate,2,4′-diphenylmethane diisocyanate and 2,2′-diphenylmethane diisocyanate;mixtures of 2,4′-diphenylmethane diisocyanate and 4,4′-diphenylmethanediisocyanate, 2,4-toluene diisocyanate, mixtures of 2,4-toluenediisocyanate and 2,6-toluene diisocyanate, 2,4′-diphenylmethanediisocyanates, 4,4′-diphenylethane diisocyanato and 1,5-naphthylenediisocyanate to mention but a few.

The suitable chain extenders used in the synthesis of polyurethanes ofthe invention are water, aliphatic difunctional or trifunctionalalcohols, amines, aminoalcohols, aminoacids, and hydroxyacids. Examplesare 2-aminoethanol, 2-dibutylaminoethanol, n-alkyl-diethanolamines,n-methyl-diethanolamine, ethylene diol, diethylene did, 1,4-butanediol,propylene diol, dipropylene did, 1,6-hexanediol, isosorbide(1,4:3,6-dianhydrosorbitol), glycerol, ethylene diamine, tetramethylenediamine, hexamethylene diamine, isophorone diamine, propanolamine,ethanolamine, glycyl-L-glutamine, glycyl-L-tyrosine, L-glutathione,glycyl glycine, L-malic acid and mixtures of these compounds.

The examples of suitable physiologically active chain extenders areoligosaccharides (chitosan-oligosaccharides with the D-glucosaminesbonded by β-1,4 bonding, maltooligosaccharides, chitoollgosaccharides),sugar alcohols, cyclodextrins creatine, modified soy, variousaminoalcohols (L-alaninol, L-asparginol, L-glutaminol, L-glycinol,L-lysinol, L-prolinol, L-tryptophanol, pyrrolidinemethanol,isoleucinol), various aminoacids, glycyl-L-glutamine, glycyl-L-tyrosine,L-glutathione, glycylglycine, L-malic acid.

The functionality of the chain extenders may relate to the followingfunctional groups: —OH, —NH₂, —SH, or —COOH.

The chain extenders have preferably a molecular weight in the range 18to 500. Preferably they have biologically and/or pharmacologicallyactive properties.

In a further embodiment a biologically and/or pharmacologically activecomponent is incorporated chemically or physically in the polymermolecule, preferably in an amount of 0.005 to 20% of the total weight ofthe biocompatible, biodegradable material.

Said biologically and/or pharmacologically active components may bechosen from: creatine, oligosaccharides (chitosan-oligosaccharides withthe D-glucosamines bonded by β-1,4 bonding, maltooligosaccharides,chitooligosaccharides), sugar alcohols, cyclodextrins, modified soy,various aminoalcohols L-asparginol, L-glycinol, L-lysinol, L-prolinol,L-tryptophanol, pyrrolidinemethanol, isoleucinol), various aminoacids,glycyl-L-glutamine, glycyl-L-tyrosine, L-glutathione, glycylglycine,L-malic acid, 2-mercaptoethyl ether, citric acid, ascorbic acid,lecithin, polyaspartates.

Typically the biocompatible, biodegradable materials degrade within 2 to18 months and preferably within 4 and 12 months.

In a further embodiment the biocompatible, biodegradable materials havea glass transition temperature in the range of −60° C. to +70° C.

Preferably the polyurethane materials—upon degradation—degrade tonontoxic by-products.

The biocompatible, biodegradable materials according to the inventionhave preferably a molecular weight in the range of 10,000 to 300,000dalton.

Typically the biocompatible, biodegradable materials have aninterconnected porous structure. The pore size is preferably in therange of 0.1 micrometer to 5000 micrometers.

The biocompatible materials according to the invention may be used forthe manufacture of implantable medical devices, in particular for micro-and/or macroporous membranous and/or spongy structures or bodies whichbay be designed as:

-   -   a scaffold suitable for bone substitute, articular cartilage        repair or soft tissue repair;    -   an artificial periosteum.    -   artificial skin or as a wound dressing.    -   a cardiovascular implant, preferably as pericardial patch or as        a vascular prostheses.    -   a bone graft substitute.    -   an articular cartilage repair.    -   a tissue engineered scaffold.

The micro- and/or macroporous membranous and/or spongy structures maycontain micrometer size or nanosize calcium phosphate crystals. Theircomplete degradation is preferably in the range of 1 month to 24 months.

The biocompatible materials according to the invention may also be usedfor the manufacture of nonporous structures for the delivery of variousdrugs. Such nonporous structures may contain a deliverable growth factoror a deliverable antibiotic or a antibacterial drug. They may bedesigned as a tissue adhesion barrier or in such a form to be suitablefor delivery of injectable polymeric and ceramic cements.

The materials according to the invention may be also designed as asurgical suture or as a an internal fixation device for bone fracturetreatment.

Further objects, features and advantages of the invention will bedescribed in more detail with reference to the following examples.

The catalysts used in the synthesis are stannous octoate and dibutyltindilaurate, but preferably ferric acetylacetonate, magnesium methoxide,zinc octoate and manganese 2-ethylhexanoate. Examples of acrylicmonomers used in the synthesis of polyurethaneacrylates of the inventionare hydroxyfunctional acrylates, such as 2-hydroxyethyl acrylate,alkoxylated hexanediol diacrylate, caprolactone-modified neopentyldiol,hydroxypivalate diacrylate, 2-hydroxyethyl acrylate, hydroxypropylacrylate, 2-hydroxyethyl methacrylate, methacrylate andglycerolmonomethacrylate.

EXAMPLE I

Linear polyurethanes were synthesized in bulk at 60° C. in a two-stepprocess. The reagents used were aliphatic hexamethylene diisocyanate,isophorone diisocyanate, poly(ε-caprolactone) diols with molecularweights of 530, 1250 and 2000, 1,4-butane diol, 2-amino-1-butanol,thiodiethylene diol, and 2-mercaptoethyl ether chain extenders, and thecatalysts were stannous octoate, dibutyltin dilaurate, ferricacetylacetonate, magnesium methoxide, zinc octoate and manganese2-ethylhexanoate. The diisocyanate to polyol and chain extender ratiowas 2:1:1. The polyurethane polymers obtained had the average molecularweights in the range of 70,000 to 280,000 dalton, the glass transitiontemperatures in the range of −38° C. to −57° C., the tensile strengthsin the range of 12 to 63 MPa and the tensile moduli in the range of 8 to107 MPa.

EXAMPLE II

Linear segmented polyester-ether urethanes withhydrophilic-to-hydrophobic ratios of 30:70, 40:60, 50:50 and 70:30% weresynthesized in bulk at temperatures in the range of 50° C. to 100° C.,using polyols with different molecular weights. The hydrophobiccomponent originated from poly(ε-caprolactone) diols with molecularweights 530, 1250, 2000 daltons, the hydrophilic component was based onpoly(ethylene oxide) diols with molecular weights of 600 and 2000daltons or poly(ethylene oxide-propylene oxide-ethylene oxide) diol withmolecular weight of 8000 daltons and polyethylene adipate with molecularweight of 1000 daltons. The diisocyanates were hexamethylenediisocyanate and isophorone diiscocyanate, the chain extenders were 1,4butane diol, 3-hexyne-2,5-diol and 2-amino-1-butanol, and the catalystused were stannous octoate and dibutyltin dilaurate. The polyurethanepolymers obtained had viscosity-average molecular weights in the rangeof 24,000 to 130,000 dalton, tensile strengths at break of 4 to 60 MPa,Young's moduli from 7 to 72 MPa, elongation at break of 100 to 950%, andglass transition temperatures in the range of −116° C. to −41° C.

EXAMPLE III

Crosslinked hydrophobic polyester urethane sponges were synthesized inbulk at temperatures in the range of 50 to 80° C., usingpoly(ε-caprolactone) diols with molecular weights 530, 1250, 2000daltons and hexamethylene diisocyanate. The chain extender was anaqueous solution of creatine and the catalyst was manganese2-ethylhexanoate. The pore-to-volume ratios in the sponges were in therange of 10 to 90%, the compressive strength in the range of 9 to 1960kPa and the compressive modulus in the range of 15 to 40 MPa.

EXAMPLE IV

Crosslinked polyurethane sponges were synthesized at temperature of 60°C., using polyethylene oxide diols with molecular weight of 600 and 2000daltons as the hydrophilic component and an aqueous solution ofcreatine. Ferric acetylacetonate was used as a catalyst. Thepore-to-volume ratios in the sponges were in the range of 50 to 70%, thecompressive strength in the range of 50 to 2000 kPa, and the compressivemodulus in the range of 11 to 35 MPa.

EXAMPLE V

The linear biodegradable aliphatic polyurethanes of varyinghydrophilicity as described in example II were subjected to swellingexperiments in water. The polymers absorbed water in an amount thatincreased with the increasing content of the hydrophilic segment in thepolymer chain. The total amount of absorbed water did not exceed 2% forthe polycaprolactone urethane and was as high as 212% for somepoly(caprolactone-ethylene oxide urethanes). Upon in vitro degradationat 37±0.1° C. in phosphate buffer solution the poly(ester urethanes)showed 1 to 2% mass loss at 48 weeks and 1.1 to 3.8% at 76 weeks. Thepolyester-ether urethanes) manifested 1.6 to 76% mass loss at 48 weeksand 1.6 to 96% at 76 weeks. The increasing content and molecular weightof the polyethylene oxide segment enhanced the rate of mass loss.Similar relations were also observed for polyurethanes from PEO-PPO-PEO(Pluronic) diols. Materials obtained using 2-amino-1-butanol as thechain extender degraded at a slower rate than similar materialssynthesized using 1,4-butane diol. All polymers calcified in vitro. Thesusceptibility to calcification increased with material hydrophilicity.

EXAMPLE VI

The linear polymers described in Examples I-II were processed intothree-dimensional porous scaffolds (membranes and sponges) using aphase-inverse process from solutions consisting of a solvent-nonsolventsystem and/or solutions containing additives of various salt crystals.

The scaffolds supported the attachment and proliferation of osteoblasts,chondrocytes and myoblasts in culture.

EXAMPLE VII

Crosslinked three-dimensional biodegradable poly ethane scaffolds(foams) with controlled hydrophilicity for bone graft substitutes weresynthesized from biocompatible reactants. The scaffolds hadhydrophilic-to-hydrophobic content ratios of 70:30, 50:50 and 30:70. Thereactants used were hexamethylene diisocyanate or tetramethylenediisocyanate, polyethylene oxide) diol with a molecular weight of 600dalton (hydrophilic component), and poly(ε-caprolactone) diol with amolecular weight of 2000 dalton, amine-based polyol with a molecularweight of 515 dalton or sucrose-based polyol with a molecular weight of445 dalton (hydrophobic component). Water alone or aqueous solutions ofcreatine, aminoalcohols or oligosaccharides were used as the chainextender and foaming agents. Stannous octoate was used as catalysts.Glycerol phosphate calcium salt, calcium carbonate and hydroxyapatitewere used as inorganic fillers. The scaffolds had an open-pore structurewith pores whose size and geometry depended on the material's chemicalcomposition. The compressive strengths of the scaffolds were in therange of 4 to 340 kPa, the compressive moduli in the range of 9 to 1960kPa. These values increased with increasing content of polycaprolactone.Of the two materials with the same amount of polycaprolactone thecompressive strengths and moduli were higher for the one containinginorganic fillers. The scaffolds absorbed water and underwent controlleddegradation in vitro. The amount of absorbed water and susceptibility todegradation increased with the increasing content of the polyethyleneoxide segment in the polymer chain and the presence in the material ofcalcium complexing moiety. All polyurethane scaffolds induced thedeposition of calcium phosphate crystals, whose structure andcalcium-to-phosphorus atomic ratio depended on the chemical compositionof the polyurethane and varied from 1.52 to 2.0.

EXAMPLE VIII

Porous scaffolds from the biodegradable aliphatic polyurethanes withvarious chemical compositions and the hydrophilic-to-hydrophobic segmentratios as described in Example V were used as cancellous bone graftsubstitutes in the treatment of monocortical and tricortical bonedefects in the ilium of healthy sheep and/or bicortical bone defects inthe ilium of estrogen-deficient sheep. Implantation times varied from 6to 25 months. The ilium defects, which were not implanted withpolyurethane scaffolds, were used as controls. In none of the controldefects there was bone regeneration at the time of euthanasia. Thedefects implanted with porous scaffolds from polyurethanes were healedto varying extents with cancellous bone. In the healthy animals the newcancellous bone was radiographically denser than the native bone Newbone formed in the scaffolds with the higher amount of the hydrophilicsegment contained more hydroxyapatite than bone in the scaffolds withthe lower hydrophilic segment content. There was no new cortex formed.In the estrogen-deficient sheep the defects implanted with polyurethanescaffolds were healed with both, the cancellous and cortical bones,although the structure of the new bone was similar to that of nativebone. The extents of bone healing were depended on the polymer chemicalcompositions.

The formation of the new cortex in the ilium defects and the restorationof the full ilium thickness were promoted when the scaffolds implantedin the defect were additionally covered with a microporous biodegradablemembrane, which guided the cortex formation and protected againstbleeding.

EXAMPLE IX

Porous scaffolds with interconnected pores were produced frombiodegradable polyurethanes according to the invention having twodifferent hydrophilic-to-hydrophobic content ratios of 70-30% and30-70%. The scaffolds with 70% of the hydrophobic component had anaverage pore size of 100-900 nm and a pore-to-volume ratio of 75%. Thescaffolds with 70% of the hydrophilic component had an average pore sizeof 100-600 nm and a pore-to-volume ratio of 84%. Cylinders 28×42 mm witha central hole along the longitudinal axis were cut from the scaffoldspacked and sterilized with a cold-cycle ETO process, followed byevacuation at 50° C. and 3×10-1 mbar for 10 hours. Subsequently thecylinders were impregnated with autogenous bone marrow and implanted incritical-size segmental defects in the sheep tibiae. At 6 months thedefects were healed with new bone which grew progressively from the cutbone ends taking over the space occupied initially by the polyurethanescaffold.

Figures 1 to 3 illustrate some of the possible embodiments of theinvention, Monocortical, bicortical and tricortical defects in the iliumare implanted with porous scaffolds “a” from biodegradable polyurethanesof the invention and covered with microporous membrane “b”. The membranecan be permanently attached to one side of the scaffold or can be placedon bone surface to cover the scaffold and attached to bone withdegradable or metallic screws or dowels. Both the membrane and thescaffold can contain various drugs such as growth factors, antibiotics,bacteriostatics, etc.

The invention claimed is:
 1. A biocompatible, biodegradable materialcomprising creatine and segmented linear polyurethane-acrylates and/orsegmented crosslinked polyurethane-acrylates, wherein said segmentedlinear polyurethane-acrylates and/or segmented crosslinkedpolyurethane-acrylates are prepared from: A) at least two biocompatiblepolyols, wherein said polyols are: (i) susceptible to hydrolytic and/orenzymatic degradation and (ii) have a molecular weight of 100 to 20,000daltons and a number of active hydroxyl groups per molecule of at leasttwo or higher; B) one or more aliphatic diisocyanates and/or aliphatictriisocyanates; C) one or more low molecular weight chain extendershaving (i) a molecular weight of 18 to 1,000 daltons and (ii) thefunctionality of at least two or higher; and D) one or morehydroxyacrylates, wherein said biocompatible, biodegradable material isin the form of a micro- and/or macroporous membranous and/or spongystructure or body.
 2. The biocompatible, biodegradable material of claim1, wherein at least two of said polyols have a different hydrophilicity.3. The biocompatible, biodegradable material of claim 1, wherein all ofsaid polyols are hydrophilic.
 4. The biocompatible, biodegradablematerial of claim 1, wherein all of said polyols are hydrophobic.
 5. Thebiocompatible, biodegradable material of claim 1, wherein at least oneof said polyols has amphiphilic qualities.
 6. The biocompatible,biodegradable material of claim 1, wherein said polyols are selectedfrom the group consisting of poly(aminobutyrate) diols,poly(ε-caprolactone) diols, poly(ethylene oxide) diols, amphiphilicpoly(ethylene oxide-propylene oxide-ethylene oxide) diols, poly(oxalatediols), aminoalcohols soy diols, cyclodextrins, aminosugars, and sugaralcohols.
 7. The biocompatible, biodegradable material of claim 1,wherein said polyols have a molecular weight in the range of 200 to10,000 daltons.
 8. The biocompatible, biodegradable material of claim 1,wherein the functionality of said chain extenders relates to thefunctional group —OH, —NH2, —SH, or —COOH.
 9. The biocompatible,biodegradable material of claim 1, wherein said chain extenders have amolecular weight in the range 18 to 500 daltons.
 10. The biocompatible,biodegradable material of claim 1, wherein said chain extenders havebiologically and/or pharmacologically active properties.
 11. Thebiocompatible, biodegradable material of claim 1, wherein the creatineis incorporated chemically in the material.
 12. The biocompatible,biodegradable material of claim 1, wherein the creatine is incorporatedphysically in the material.
 13. The biocompatible, biodegradablematerial of claim 1, wherein the creatine is present in an amount of0.005% to 20% of the total weight of the material.
 14. Thebiocompatible, biodegradable material of claim 1, further comprising oneor more biologically and/or pharmacologically active components selectedfrom the group consisting of oligosaccharides (chitosan-oligosaccharideswith the D-glucosamines bonded by β-1,4 bonding, maltooligosaccharides,chitooligosaccharides), sugar alcohols, cyclodextrins, modified soy,various aminoalcohols (L-alaninol, L-asparginol, L-glutaminol,L-glycinol, L-lysinol, L-prolinol, L-tryptophanol, pyrrolidinemethanol,isoleucinol), various aminoacids, glycyl-L-glutamine, glycyl-L:tyrosine, L-glutathione, glycylglycine, L-malic acid, 2-mercaptoethylether, citric acid, ascorbic acid, lecithin, and polyaspartates.
 15. Thebiocompatible, biodegradable material of claim 1, wherein said aliphaticdiisocyanates are selected from the group consisting of1,6-hexamethylene diisocyanate, 1,4-diisocyanato butane, L-lysinediisocyanate, isophorone diisocyanate, 1,4-diisocyanato 2-methyl butane,2,3-diisocyanato 2,3-dimethyl butane, 1,4-di(1propoxy-3-diisocyanate,1,4-diisocyanato 2-butene, 1,10-diisocyanato decane, ethylenediisocyanate, 2,5 bis(2-isocyanato ethyl) furan, 1,6-diisocyanato2,5-diethyl hexane, 1,6-diisocyanato 3-methoxy hexane, 1,5 diisocyanatopentane, 1,12-dodecamethylene diisocyanate, 2 methyl-2,4 diisocyanatopentane, 2,2 dimethyl-1,5 diisocyanato pentane, ethyl phosphonyldiisocyanate, 2,2,4-trimethyl-1, 6-hexamethylene diisocyanate,4,4′-dicyclohexylmethane diisocyante (H₁₂MDI), trans 1,4-cyclohexanediisocyanate, m-tetramethylxylylen diisocyanate,m-isopropenyldimethylbenzyl, “dimeryl” diisocyanate derived fromdimerized linoleic acid, xylylene diisocyanate, and1,1,6,6-tetrahydroperfluorohexamethylene diisocyanate.
 16. Thebiocompatible, biodegradable material of claim 1, wherein said chainextenders are selected from the group consisting of water,thiodiethylene diol, 2-mercaptoethyl ether, isosorbide diols, citricacid, ascorbic acid, aminobutyric acid, aminoethanol, 2-aminoethanol,2-dibutylaminoethanol, n-alkyl-diethanolamines, n-methyl-diethanolamine,ethylene diol, diethylene diol, 1,4-butanediol, propylene diol,dipropylene diol, 1,6-hexanediol, 1,4:3,6-dianhydro-D-sorbitol,1,4:3,6-dianhydro-D-mannitol, 1,4:3,6-dianhydro-L-iditol, glycerol,ethylene diamine, tetramethylene diamine, hexamethylene diamine,isophorone diamine, pro-panolamine, ethanolamine, glycyl-L-Glutamine,glycyl-L-tyrosine, L-Glutathione, glycylglycine, L-malic acid, andmixtures of these compounds.
 17. The biocompatible, biodegradablematerial of claim 1, which has a hard segment content in the range of 5%to 100% and a soft segment which forms the remaining part of thematerial.
 18. The biocompatible, biodegradable material of claim 1,which has amphiphilic properties.
 19. The biocompatible, biodegradablematerial of claim 1, having a ratio of hydrophilic polyols tohydrophobic polyols in the range of 2:1 to 2.6:1.
 20. The biocompatible,biodegradable material of claim 1, which degrades within 2 to 18 monthsor within 4 to 12 months.
 21. The biocompatible, biodegradable materialof claim 1, which has a glass transition temperature in the range of−60° C. to +70° C.
 22. The biocompatible, biodegradable material ofclaim 1, which, upon degradation, degrades into nontoxic by-products.23. The biocompatible, biodegradable material of claim 1, which has amolecular weight in the range of 10,000 to 300,000 dalton.
 24. Thebiocompatible, biodegradable material of claim 1, wherein the membranousand/or spongy structure or body contains pores having a pore size in therange of 0.1 to 5,000 micrometers.
 25. The biocompatible, biodegradablematerial of claim 1, which is designed as a scaffold suitable for bonesubstitute, articular cartilage repair or soft tissue repair.
 26. Thebiocompatible, biodegradable material of claim 1, which is designed asan artificial periosteum.
 27. The biocompatible, biodegradable materialof claim 1, which is designed as artificial skin or as a wound dressing.28. The biocompatible, biodegradable material of claim 1, which isdesigned as a cardiovascular implant, pericardial patch or a vascularprostheses.
 29. The biocompatible, biodegradable material of claim 1,which is designed as a bone graft substitute.
 30. The biocompatible,biodegradable material of claim 1, which is designed as an articularcartilage repair.
 31. The biocompatible, biodegradable material of claim1, which is designed as a tissue engineered scaffold.
 32. Thebiocompatible, biodegradable material of claim 1, which containsnanosize or micrometer size calcium phosphate crystals.
 33. Thebiocompatible, biodegradable material of claim 1, which completelydegrades after a time period in the range of 1 to 24 months.
 34. Thebiocompatible, biodegradable material of claim 1, which is designed asan internal fixation device for bone fracture treatment.